Takaaki Tokito

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy.

BACKGROUND Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT). METHODS We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis. RESULTS Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups. CONCLUSIONS Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.

Significance of Programmed Cell Death-Ligand 1 Expression and its Association with Survival in Patients with Small Cell Lung Cancer

Background: Programmed cell death 1 receptor–ligand interaction is a major pathway often hijacked by tumors to suppress immune control. The aim of this retrospective study was to investigate the prevalence and prognostic roles of programmed cell death -ligand 1 (PD-L1) expression in small cell lung cancer (SCLC). Methods: The expression of PD-L1 was evaluated by immunohistochemical analysis in 102 specimens of SCLC. Tumors with staining in over 5% of tumor cells were scored as positive for PD-L1 expression. Survival analysis was performed using the Kaplan–Meier method. Results: Expression of PD-L1 in tumor cells was observed in 71.6% (73 of 102) of SCLCs, and was significantly correlated with a limited disease (LD) stage. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than those with PD-L1-negative (median OS, 16.3 versus 7.3 months; p < 0.001, respectively). Multivariate analyses demonstrated that a good performance status, LD stage, and expression of PD-L1 were significantly predictive of better OS, independently of other factors. We found no relevance between PD-L1 expression and progression-free survival for first-line treatment in LD- and extensive disease-SCLC patients. Conclusions: In patients with SCLC, expression of PD-L1 is positively correlated with a LD stage, and is independently predictive of a favorable outcome.

Digital PCR analysis of plasma cell-free DNA for non-invasive detection of drug resistance mechanisms in EGFR mutant NSCLC: Correlation with paired tumor samples

As the development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has become an issue of concern, identification of the mechanisms responsible has become an urgent priority. However, for research purposes, it is not easy to obtain tumor samples from patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) that has relapsed after treatment with EGFR-TKIs. Here, using digital PCR assay as an alternative and noninvasive method, we examined plasma and tumor samples from patients with relapsed NSCLC to establish the inter-relationships existing among T790M mutation, activating EGFR mutations, HER2 amplification, and MET amplification. Paired samples of tumor and blood were obtained from a total of 18 patients with NSCLC after they had developed resistance to EGFR-TKI treatment, and the mechanisms of resistance were analyzed by digital PCR. Digital PCR analysis of T790M mutation in plasma had a sensitivity of 81.8% and specificity of 85.7%, the overall concordance between plasma and tissue samples being 83.3%. MET gene copy number gain in tumor DNA was observed by digital PCR in three patients, of whom one exhibited positivity for MET amplification by FISH, whereas no patient demonstrated MET and HER2 copy number gain in plasma DNA. Digital PCR analysis of plasma is feasible and accurate for detection of T790M mutation in NSCLC that becomes resistant to treatment with EGFR-TKIs.

Association of EGFR Exon 19 Deletion and EGFR-TKI Treatment Duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients

The most common event responsible for resistance to first- and second-generation (1st and 2nd) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is acquisition of T790M mutation. We examined whether T790M is related to clinicopathologic or prognostic factors in patients with relapse of EGFR mutant non-small cell lung cancer (NSCLC) after treatment with 1st or 2nd EGFR-TKIs. We retrospectively reviewed the T790M status and clinical characteristics of 73 patients with advanced or recurrent NSCLC who had been treated with EGFR-TKIs and undergone rebiopsy at Kurume University Hospital between March 2005 and December 2015. T790M mutation was more frequent in patients with EGFR exon 19 deletion mutation (63%, 26/41) than in those with L858R mutation (38%, 12/32) (p = 0.035). The median total duration of 1st or 2nd EGFR-TKI treatment was significantly longer in patients with T790M mutation than in those without (15.3 months vs 8.1 months, p < 0.001). Multivariate analysis revealed that the type of EGFR mutation and the total duration of EGFR-TKI treatment were significantly associated with T790M prevalence. Patients with EGFR exon 19 deletion mutation who receive long-term EGFR-TKI therapy show a high prevalence of T790M mutation. The present data are potentially important for clinical decision-making in NSCLC patients with EGFR mutation.

Toxicity and efficacy of chemotherapy for non-small cell lung cancer with cavitary lesions

BACKGROUND Concurrent chemoradiation in stage III non-small cell lung cancer (NSCLC) patients with cavitary lesions is reported to cause serious lung complications and is a predictor of poor survival. However, the efficacy and toxicity associated with chemotherapy for advanced NSCLC patients with cavitary lesions is not clear. We investigated the toxicities, particularly hemoptysis and cavity infection, and efficacy associated with chemotherapy for NSCLC patients with cavitary lesions. METHODS We retrospectively reviewed consecutive patients who received first-line chemotherapy, including platinum-based chemotherapy, single-agent chemotherapy, or epidermal growth factor receptor-tyrosine kinase inhibitors, at our institution between January 2008 and December 2010. RESULTS We found tumor cavitation prior to treatment in 23 of 415 NSCLC patients (5.5%). The response rate of all the patients was 30%, and the median survival time (MST) was 8.9 months. The MST of the 15 patients treated with platinum-based chemotherapy was 11 months. Grade 1 bronchopulmonary hemorrhage occurred in 2 patients. Grade 3 cavitary infection occurred in 2 patients, resulting in the discontinuation of chemotherapy. CONCLUSIONS This study indicates that the toxicity of chemotherapy for NSCLC patients with cavitary lesions is tolerable; however, the development of cavitary infection should be carefully considered. In addition, this study suggests that the efficacy of chemotherapy for NSCLC patients with cavitary lesions is similar to the response rates reported in the literature; however, the survival of these patients may be worse than that for general NSCLC patients.

Programmed cell death-ligand 1 expression and immunoscore in stage II and III non-small cell lung cancer patients receiving adjuvant chemotherapy

Programmed cell death 1 (PD-1) receptor-ligand interaction is a major pathway that is often hijacked by tumors to suppress immune control. Immunoscore (IS), a combinational index of CD3 and CD8 tumor-infiltrating lymphocyte (TIL) density in the tumors center and invasive margin, is a new prognostic tool suggested to be superior to conventional tumor-staging methods in various tumors. This retrospective study aimed to investigate the prevalence and prognostic roles of PD-ligand 1 (PD-L1) expression and IS in non-small cell lung cancer (NSCLC) patients receiving adjuvant chemotherapy. PD-L1 expression and TIL density were evaluated by immunohistochemical analysis in 36 patients with stage II and III NSCLC. Tumors with staining in over 1% of their cells were scored as positive for PD-L1 expression, and we determined the median number of CD3- and CD8-positive TILs as the cutoff point for TIL density. To determine IS, each patient was given a binary score (0 for low and 1 for high) for CD3 and CD8 density in both the tumor center and invasive margin region. PD-L1 expression in tumor cells was observed in 61.1% (22/36) of patients. PD-L1 expression was significantly associated with high IS, and highest IS tended to have a favorable disease-free survival.Programmed cell death 1 (PD-1) receptor–ligand interaction is a major pathway that is often hijacked by tumors to suppress immune control. Immunoscore (IS), a combinational index of CD3 and CD8 tumor-infiltrating lymphocyte (TIL) density in the tumor’s center and invasive margin, is a new prognostic tool suggested to be superior to conventional tumor-staging methods in various tumors. This retrospective study aimed to investigate the prevalence and prognostic roles of PD-ligand 1 (PD-L1) expression and IS in non-small cell lung cancer (NSCLC) patients receiving adjuvant chemotherapy. PD-L1 expression and TIL density were evaluated by immunohistochemical analysis in 36 patients with stage II and III NSCLC. Tumors with staining in over 1% of their cells were scored as positive for PD-L1 expression, and we determined the median number of CD3- and CD8-positive TILs as the cutoff point for TIL density. To determine IS, each patient was given a binary score (0 for low and 1 for high) for CD3 and CD8 density in both the tumor center and invasive margin region. PD-L1 expression in tumor cells was observed in 61.1% (22/36) of patients. PD-L1 expression was significantly associated with high IS, and highest IS tended to have a favorable disease-free survival.

Accuracy of transbronchial biopsy as a rebiopsy method for patients with relapse of advanced non-small-cell lung cancer after systemic chemotherapy

Introduction Rebiopsy in patients with advanced non-small-cell lung cancer (NSCLC) resistant to systemic chemotherapy may yield information on the mechanisms of resistance and planning of subsequent treatment. Transbronchial biopsy (TBB) using a flexible bronchoscope has been commonly used for establishing the initial diagnosis of lung cancer. The aim of this study was to assess the accuracy and safety of TBB in patients with NSCLC relapse, and the factors affecting its diagnostic yield. Methods We retrospectively screened patients with advanced NSCLC who underwent TBB for rebiopsy after developing resistance to systemic chemotherapy at Kurume University Hospital between January 2012 and June 2016. A positive diagnostic result obtained by TBB was defined as malignancy determined on the basis of histological features that were adequate for mutational analysis or immunohistochemistry. Severe postprocedural complications were defined as those requiring invasive medical procedures or prolonged hospitalisation. Results 109 patients were enrolled in this retrospective study. Adequate tumour samples were collected from 88 of these patients, giving a high diagnostic yield of 80.7%. The diagnostic yield of TBB was not associated with tumour mutational status, the previous treatment regimen, or efficacy of the previous treatment. There were no severe postprocedural complications such as pneumothorax or serious haemorrhage. Conclusions TBB is considered one of the safest and most useful procedures for rebiopsy of NSCLC that has relapsed after chemotherapy, regardless of patient background and treatment history.

Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients

BACKGROUND Cisplatin plus pemetrexed is a standard front-line chemotherapeutic regimen for inoperable malignant pleural mesothelioma (MPM). However, no clinical trials have compared the efficacy of cisplatin plus pemetrexed and cisplatin plus gemcitabine, which may be comparable based on previous phase II study results. This study aimed at evaluating the efficacy of cisplatin plus pemetrexed and comparing it with that of cisplatin plus gemcitabine in Japanese MPM patients. METHODS From July 2002 to December 2011, 13 and 17 consecutive patients with inoperable MPM were treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed, respectively, at the Shizuoka Cancer Center. We reviewed the medical charts of these patients and evaluated their characteristics as well as data regarding drug toxicity and antitumor efficacy. RESULTS The response rates were 15% and 35% in the cisplatin plus gemcitabine and cisplatin plus pemetrexed groups, respectively (P=0.4069), while disease control rates were 77%, and 82%, respectively (P=0.9999). Progression-free survival was significantly higher with cisplatin plus pemetrexed (median, 215.5 days) than with cisplatin plus gemcitabine (median, 142.5 days) (P=0.0146; hazard ratio [HR], 0.3552). Overall survival showed a tendency towards being superior with cisplatin plus pemetrexed (median, 597.5 days) compared with cisplatin plus gemcitabine (median, 306.5 days) (P=0.1725, HR, 0.5516). Hematological toxicities, especially thrombocytopenia and neutropenia, tended to be more frequent and severe in the cisplatin plus gemcitabine group. CONCLUSIONS Cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM.

Complication of bovine pericardial buttress: pulmonary pseudotumor.

A 38-year-old man reported progressive back pain 4 years after undergoing partial resection of the lung for spontaneous pneumothorax, using staples buttressed with bovine pericardium. Chest computed tomography detected a mass near the staple line. Resection of the mass was performed successfully and the pain was relieved. The excised material was identified as an inflammatory pulmonary pseudotumor caused by the buttressing material.

Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab with Maintenance Bevacizumab as a First-line Treatment for Advanced Non-squamous Non-small Cell Lung Cancer in Elderly Patients

Background/Aim: The combination of platinum-doublet chemotherapy with bevacizumab has been established as a first-line treatment option in non-elderly patients with non-squamous (non-sq) non-small cell lung cancer (NSCLC). However, the safety and efficacy of this regimen have not yet been fully established in elderly patients. Patients and Methods: Chemo-naïve patients with non-sq NSCLC, aged ≥75 years, having a good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were considered eligible. Patients received carboplatin (area under the curve=5 mg/ml/min), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) every 3 weeks for up to 4 cycles, followed by maintenance bevacizumab. The primary endpoint was the objective response rate (ORR; target=50%, threshold=30%; Simons two-stage design), and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were enrolled from June 2013 to July 2017. The study was closed because of slow patient accrual. The median patient age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved a partial response (PR), yielding an ORR of 58%. The median PFS was 8.4 [95% confidence interval (CI)=4.4-10.5] months, and the median OS was 33.9 (95%CI=13.2-43.3) months. Toxicities were generally mild and consistent with previous reports. There were no treatment-related deaths. Conclusion: A regimen comprising carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and potentially efficacious in elderly patients with non-sq NSCLC.